Obstructive sleep apnea (OSA) is a highly prevalent condition with major neurocognitive and cardiovascular sequelae. Despite its recognized consequences, the treatment of this condition remains unacceptable as the existing therapies are poorly tolerated and/or have highly variable efficacy. The role of the arousal threshold has received minimal attention in the OSA literature; despite recent recognition that the propensity to wake up from sleep may have a major pathophysiological role is OSA. The accumulation of respiratory stimuli during sleep can activate upper ainway muscles to preserve pharyngeal patency, but can only do so if sufficient time is available for 002 and negative pressure to develop. That is, premature awakening could lead to recurrent arousals and prevent the stabilization of pharyngeal patency during sleep. The present application will study differences in arousal threshold between OSA and matched controls (Aim 1), and the reversibility of abnormalities in OSA with CPAP therapy (Aim 2). The role of non-myorelaxant hypnotic therapy will also be assessed from standpoint of the effects on upper ainway mechanics and control (Aim 3) and therapeutic effects on short-term clinical outcome (Aim 4). Our research will interact heavily with all of the other Projects within this PPG by providing clinical relevance to the basic research regarding the role of the parabrachial complex on arousal from sleep. In addition, the proposed rodent experiments by our collaborators will provide mechanistic insights into the arousal response which would involve studies neither feasible nor ethical in humans. Project 2 will therefore define the potential role of the arousal threshold in OSA pathogenesis and its viability as a therapeutic target in OSA, at least for a subgroup of patients.